Psoriasis is a disfiguring and debilitating disease for which no standard treatment exists. Existing topical treatments are effective, but unacceptable side-effects, diminished effectiveness over time and inconvenience prevent long-term usage. The emergence of effective biologies, such as anti-TNF and anti-LFA inhibitors, offer superior treatment options for many psoriasis patients, but concerns over the side-effects resulting from down-regulation of the immune response temper their enthusiastic use. The purpose of this proposal is to develop RNA-based therapeutics that specifically inhibits genes important in psoriasis pathogenesis, which can be applied topically to affected areas of the skin. Topical application allows delivery of higher concentrations of drug with diminished concerns regarding side-effects. Phase I builds on recently developed formulations to show that nucleic acids can be effectively delivered to mouse skin and that a reporter gene and TNF (a validated psoriasis drug target) can be blocked by specific, robust RNA inhibitors. The RNA inhibitors to be developed and tested include SomaGenics1 proprietary Lassos, which specifically bind to and covalently circularize around an mRNA target, and small hairpin RNAs that work through an RNA interference mechanism. Phase II aims to develop these RNA inhibitors against additional relevant psoriasis gene targets and show their effectiveness in a human skin organ model in preparation for a Phase 1 clinical trial. The development of a topical formation containing effective psoriasis inhibitors would fill a currently unmet medical need.